In this study, we propose that the monocytes/macrophages may be heavily involved in the pathogenesis and progression to AIDS during HIV infection. Our preliminary data show a high monocyte turnover in SIV infected animals compared to control uninfected animals. Massive destruction of tissue macrophages evident in the lymph node of an infected monkey was strongly suggested as the cause of the high monocyte turnover. More importantly, in a longitudinal study of a small cohort of four SIV-infected monkeys, the animal that demonstrated early high and sustained monocyte turnover was a rapid progressor and died with AIDS despite similar levels of T cell activation, high viral load and CD4 counts compared to the other animals in the cohort. Therefore, in this study we propose to infect 8 rhesus macaques with pathogenic SIV251 virus to demonstrate in detail if changes in the magnitude of the monocyte turnover will in fact predict AIDS disease progression. Moreover, the mechanism of the monocyte turnover will be studied. The notion that monocyte turnover is important in AIDS progression was strongly supported by the fact that when either all chronically infected animals that died with AIDS (diagnosed by pathology) or animals that are still alive were analyzed for the survivor time after BrdU injection, the only parameter that predicted progression to AIDS with statistical significance was high monocyte turnover (see preliminary data). Our hypothesis is that the progressive destruction of tissue macrophages by SIV/HIV is one of the major factors that dictate AIDS disease progression. A corollary to this hypothesis is that the high monocyte turnover in blood is a result of massive destruction of tissue macrophages and may be a predictor of AIDS disease progression. PUBLIC HEALTH RELEVANCE: It is widely accepted that destruction of CD4+ T cells is the primary cause of immunodeficiency manifested by opportunistic infections in HIV-1 infected humans as well as in SIV-infected macaques. However, the mechanisms that dictate the tempo of disease progression have yet to be elucidated. Not all infected individuals with low CD4 count progress similarly to AIDS. Macrophages, an important cell component of the innate immune system and link between innate and adaptive immunity, are also important targets of HIV/SIV infection. In the proposed application, the role of monocyte/macrophage lineage cells in the pathogenesis of AIDS will be examined in the SIV/rhesus macaque animal model. We propose that not only the CD4 T cells but also the monocytes/macrophages are involved in the pathogenesis and progression to AIDS during HIV infection.